aInstitute of Molecular Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan;qCenter of Precision Medicine, College of Medicine, National Taiwan University, 10002 Taipei, Taiwan

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Significance

It is known that nutrient starvation stimulates mitochondrial fusion for cell survival. In this study, a homozygous mutation in the NME3 gene, which encodes an NDP kinase, was identified in a fatal neurodegenerative disorder. Cells derived from the patient were deficient of NME3 and intolerant to glucose starvation. Patient cells were used to demonstrate that NME3 rescued cell survival by two separate functions, namely stimulation of mitochondrial fusion and NDP kinase activity. Since mitochondrial dynamics and energy efficiency are important for neuronal development, our data suggest a link between two functions of NME3 and a fatal neuronal disorder.

Abstract

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient’s fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient’s cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

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